The degree of behavioral control which an organism has over a stressor (ability to alter the onset, termination, duration, intensity, or temporal pattern of the event) is an important determinant of the behavioral and physiological impact of the stressor. Numerous behavioral, neurochemical, hormonal, and immunological changes follow exposure to a stressor if it is uncontrollable, but not if the identical stressor is controllable. Effects such as these which depend on the uncontrollability of a stressor have been called "learned helplessness effects." They have played an important role in psychological theory, in understanding the physiology of stress, in understanding the environmental regulation of endogenous pain modulation mechanisms and immune function, and have been proposed to be involved in the etiology of numerous human disorders. Depression, anxiety disorders, and post-traumatic stress disorder are but examples. Despite the seeming importance of stressor controllability and the considerable amount of research that has ben directed at explaining its operation, there is still no adequate general explanation at either the behavioral or physiological level. The present proposal is designed to directly test an integrated behavioral and physiological explanation of learned helplessness effects that has emerged during the previous grant period. This hypothesis includes both a description of the immediate neurochemical effects of uncontrollable stressors as well as a putative set of mechanisms for how the behavioral sequalae of such stressors are produced. At a behavioral level the critical argument is that uncontrollable stressors produce intense "anxiety" that dissipates over a 3-5 day period, and that many of the behavioral consequences of these stressors reflect this state of anxiety. At a physiological level it is argued that this state of anxiety involves a temporarily hyper-responsive serotonergic (5-HT) system originating from the dorsal raphe nucleus (DRN) and that the diverse behavioral outcomes of exposure to uncontrollable stressors are produced by excessive 5-HT released in projections of the DRN.